Aminosalicylate Therapy

Introduction

Aminosalicylate (5-ASA) therapy is often the first treatment option for patients presenting with mild to moderate ulcerative colitis (UC). Symptom improvements can be observed within 2 to 4 weeks following treatment initiation and once remission is achieved, 5-ASAs are typically continued as maintenance. Treatment is often very well tolerated and is not associated with an increased risk of infection or malignancy. The safety and efficacy of the 5-ASA agents, as well as prescribing considerations, are discussed herein.

Mechanism of Action

Although the exact mechanism by which 5-ASA has clinical efficacy in the treatment of UC is not completely understood, it is proposed to be due to several of its anti-inflammatory properties, including the induction of peroxisome proliferator-activated receptor gamma (PPAR-g) gene expression, inhibition of cyclo-oxygenase synthesis, prostaglandin synthesis, chemotactic leukotriene synthesis, IL-1 synthesis and nuclear factor kappaB activation, scavenging of reactive oxygen species and others.

Types of 5-ASA Agents

Since 5-ASA acts topically, minimizing systemic absorption from the small intestine and maximizing delivery to the site of inflammation have been key factors governing the development of new 5-ASA agents and formulations. Sulfasalazine, the first 5-ASA, consists of 5-ASA azo-bonded to a sulfapyridine molecule, which confers resistance to gastric breakdown and limits bioavailability in the upper gastrointestinal (GI) tract. In the colon, intestinal bacteria cleave the azo bond and release its constituent moieties, including the bioactive 5-ASA component. Sulfasalazine is still used today, but adverse reactions associated with its sulfa component, such as nausea and headache, led to the development of other non–sulfa-containing formulations: olsalazine, balsalazide and mesalamine (Figure 8-1). Olsalazine and balsalazide employ similar 5-ASA release strategies. Olsalazine consists of two 5-ASA molecules azo-bonded together, whereas balsalazide is aso-bonded to an inert benzoic acid derivative carrier molecule, 4-aminobenzoyl-β-alanine. As such, like sulfasalazine, olsalazine and balsalazide are dependent on anaerobic bacteria of the colon to cleave the azo bond. However, unlike sulfasalazine, neither contain sulfa moieties. Currently, there is a single Food and Drug Administration (FDA)-approved olsalazine-containing medicinal product (Dipentum) and two balsalazide-containing medicinal products (Colazal, Giazo) for UC.

Compared to the other 5-ASA agents, mesalamine is unique in that the 5-ASA molecule is not bonded to another module. Instead, the different mesalamine-containing formulations enclose it within a protective covering that resists gastric breakdown. Various formulations of mesalamine have been developed, which impact where the active component starts to be released and how frequently the medications needs to be taken.

Currently, there are five FDA-approved mesalamine-containing oral formulations (Apriso, Asacol HD, Delzicol, Lialda, Pentasa) and two rectal formulations (Canasa, Rowasa/SfRowasa) for UC. Several of the oral formulations (Apriso, Asacol HD, Delzicol) enclose mesalamine within an enteric coat than resists gastric breakdown until the jejunum or terminal ileum and cecum, where the pH causes the protective coat to disintegrate, releasing 5-ASA. Pentasa consists of microspheres of 5-ASA enclosed within a moisture-sensitive, ethylcellulose, semipermeable membrane that permits pH-independent release of 5-ASA, starting from the duodenum and continuing throughout the entire length of the GI tract. Lialda first employs a pH-dependent coating, delaying release until the terminal ileum. Once pH 7 or higher is reached, the acid-resistant coating disintegrates and a lipophilic- and hydrophilic-rich MMX core prolongs release throughout the rest of the colon.

If disease activity is restricted to left-sided colon, then topical therapy with an enema (Rowasa/SfRowasa) or suppository (Canasa) is effective at inducing and maintaining remission. Additionally, oral mesalmine derivatives have been shown to be effective for induction and maintenance of remission in patients with left-sided disease. Suppositories are effective for up to between 15 cm and 20 cm, whereas enemas can reach up to the splenic flexure.

The different formulations of oral 5-ASA agents have implications on how these medications should be taken (Table 8-1). Formulations with enteric coating must be swallowed whole, since their protective coating is what allows them to be released at the correct location of the GI track. Patients should therefore be advised not to chew, cut, or crush tablets or capsules. Similarly, Lialda is designed to be swallowed whole, since it utilizes a distinct type of protective coating. Delzicol and Pentasa may be more suitable for patients who have a difficult time swallowing their medicine whole, since the contents of these capsules may be removed and swallowed instead. Colazal tablets may also be suitable for such patients, since the capsule contents may be sprinkled on applesauce and chewed. Although this is commonly done and is an FDA-approved alternative method of administration, this approach has not been tested in clinical trials. Most 5-ASA agents have been found to be comparably efficacious, so patient preferences and other factors that affect compliance are important to consider when deciding on an appropriate treatment regimen.

In patients with distal disease distribution, from the splenic flexure to the rectum, enemas and suppositories are good options that deliver 5-ASA directly to the site of inflammation, while minimizing systemic absorption. However, these formulations have their own drawbacks, including undesirable adverse reactions, such as abdominal bloating and leakage. In addition, many patients are hesitant to use these formulations or find them impractical. As a result, compliance can be an issue. Although many patients prefer oral 5-ASA agents due to their ease of administration, compliance issues exist for these formulations as well, since many have multiple-daily dosing regimens, requiring many tablets to achieve therapeutic efficacy. Noncompliance is especially an issue during periods of disease quiescence. Once-daily formulations, including Apriso and Lialda, are available and may be useful for patients with known or suspected compliance issues. It is important to recognize that oral mesalamine is effective for treatment of left-sided UC.

In patients with extensive mild to moderate UC, oral 5-ASA agents are the mainstay for induction and maintenance of remission. However, even in extensive disease, the greatest efficacy for the treatment of active UC is seen when a topical 5-ASA agent is added to oral therapy.

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Efficacy

Oral 5-ASA Agents for Induction and Maintenance

A 2016 Cochrane review of 53 studies enrolling a total of 8,548 patients evaluated the efficacy, dose-responsiveness and safety of oral 5-ASA agents compared to placebo, sulfasalazine and other 5-ASA comparators in inducing remission in active UC. Although 5-ASA agents were significantly superior to placebo in terms of all efficacy measures evaluated, newer 5-ASA agents were not more efficacious than sulfasalazine. Once-daily dosing of 5-ASA agents was no less effective than conventionally dosed regimens (ie, according to the label). Surprisingly, once-daily dosing did not improve adherence, at least in the clinical trial setting. No significant differences were observed in the incidence of adverse events between 5-ASA agents and placebo or between once-daily dosing and conventional dosing regimens. However, adverse events were more common in patients treated with sulfasalazine compared to newer 5-ASA agents (29% vs 15%; RR 0.48).

Another 2016 Cochrane review assessed the efficacy and safety of oral 5-ASA agents, as described above, for the maintenance of remission in quiescent UC. This analysis included 41 studies enrolling a total of 8928 patients. For maintenance of clinical or endoscopic remission, 5-ASA agents were significantly superior to placebo. A significant benefit was observed in subgroups of patients who received a higher dose of 5-ASA agents, specifically 1 g/day to 1.9 g/day (RR 0.65) and ≥2 g/day (RR 0.73). As such, patients with extensive UC or with frequent relapses may benefit from higher-dose maintenance therapy. Differences in efficacy were not observed between newer 5-ASA formulations; however, sulfasalazine was found to be more efficacious than newer 5-ASA agents (48% relapse vs 43% relapse with sulfasalazine; RR 1.14). In terms of dosing frequency, no significant differences in efficacy were observed between once-daily and conventional dosing regimens. No significant differences in frequency of adverse events were observed between 5-ASA agents and placebo, between once-daily dosing and conventional dosing regimens, or between high- and low-dose regimens. Although no differences in incidence of adverse events were observed between newer 5-ASA agents and sulfasalazine, these trials were biased in favor of sulfasalazine, since they enrolled patients with known sulfasalazine tolerance.

Rectal 5-ASA Agents for Induction and Maintenance

In a 2010 Cochrane review of 38 studies, the safety and efficacy of rectal 5-ASA agents were assessed in patients with active distal UC. Compared to placebo, rectal 5-ASA agents were superior for inducing symptomatic, endoscopic and histological improvement in remission. Rectal 5-ASA agents were also superior to rectal corticosteroids for inducing symptomatic improvement and remission. No difference in symptomatic improvement was observed between oral and rectal 5-ASA agents. Treatment response was not affected by 5-ASA formulation or total daily doses. The combination of oral and rectal agents appeared to be more effective than either treatment alone for induction.

A 2012 Cochrane review of nine studies enrolling 484 patients assessed the safety and efficacy of rectal 5-ASA agents in the maintenance of remission in distal UC. Liquid enemas were used in five studies and suppositories were used in four studies. Rectal 5-ASA agents were superior to placebo for maintenance of remission and endoscopic remission over a 12-month period. No differences were observed between rectal 5-ASA and placebo groups in the frequency of adverse events (16% rectal 5-ASA vs 12% placebo). No significant differences were observed between rectal and oral 5-ASA groups for symptomatic or endoscopic remission over a 6-month period.

Safety

Overall, 5-ASA agents are safe and well-tolerated, with few contraindications. The most commonly reported adverse events associated with oral 5-ASA agents during induction and maintenance therapy include flatulence, abdominal pain, nausea, diarrhea, headache, worsening UC, dyspepsia and nasopharyngitis. The most commonly reported adverse events with rectal 5-ASAs include anal irritation and abdominal pain.

Sulfasalazine is generally associated with a greater frequency of adverse reactions compared to the newer 5-ASA agents. Men taking sulfasalazine should discontinue treatment 6 weeks prior to trying to conceive due to its reversible effects on sperm count. Sulfasalazine can also impair folate metabolism, therefore patients should take supplemental folic acid while on therapy. Although there are no well-controlled studies in pregnant women, most 5-ASA agents–with the exception of Asacol HD and Dipentum (olsalazine)–have failed to demonstrate a risk to the fetus in animal reproduction studies; however, potential benefits may warrant use in pregnant women despite the potential risks. Note that although 5-ASAs are excreted in breast milk, they can still be considered for use in nursing women if the benefits outweigh the risks.

In rare instances, 5-ASA agents have caused renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis and, rarely, renal failure. As such, it is recommended that patients’ renal function be evaluated prior to treatment initiation and periodically throughout treatment. Caution should be exercised in patients with known renal dysfunction or a history of renal disease.

Summary

Altogether, 5-ASA therapy remains the best initial treatment option for patients with mild to moderate UC.A combination of oral and rectal treatment is often more effective than one approach alone. With perhaps the exception of sulfasalazine, which is associated with a greater risk for adverse reactions, there appear to be few differences in terms of efficacy between the 5-ASA therapies. As such, the initial treatment should be based on patient preference, tolerance and an ability to comply to the prescribed dosing regimen.